Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

Tiaden, André N.; Breiden, Maike; Mirsaidi, Ali; Weber, Fabienne A.; Bahrenberg, Gregor; Glanz, Stephan; Cinelli, Paolo; Ehrmann, Michael; Richards, Peter J.

doi:10.1002/stem.1190

Cited by 62 publications

(72 citation statements)

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“…Most recently, the isolation of ASCs from human cadaveric adipose tissue and their adherence and survival on demineralized bone allografts has been reported [69], suggesting that viable ASCs for osteogenic differentiation may also be obtained from cadavers within 24 hours of their death. Using in vitro culture systems, the expression patterns of key osteogenic genes have been assessed using livecell, temporal gene expression analysis of ASC osteogenesis under dexamethasone/VD3 induction [70], and numerous studies characterize the role of key signaling pathways in this lineage [71][72][73][74][75][76][77][78]. Recent studies have expanded upon this work to identify the role of miRNA in this lineage, identifying putative roles for miRNAs such as miR-22, miR-17, miR-637, and miR-196a in osteogenesis [79][80][81][82].…”

Section: The Mesodermal Potential Of Ascsmentioning

confidence: 99%

Adipose-Derived Stem Cells in Tissue Regeneration: A Review

2013

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In 2001, researchers at the University of California, Los Angeles, described the isolation of a new population of adult stem cells from liposuctioned adipose tissue. These stem cells, now known as adipose-derived stem cells or ADSCs, have gone on to become one of the most popular adult stem cells populations in the fields of stem cell research and regenerative medicine. As of today, thousands of research and clinical articles have been published using ASCs, describing their possible pluripotency in vitro, their uses in regenerative animal models, and their application to the clinic. This paper outlines the progress made in the ASC field since their initial description in 2001, describing their mesodermal, ectodermal, and endodermal potentials both in vitro and in vivo, their use in mediating inflammation and vascularization during tissue regeneration, and their potential for reprogramming into induced pluripotent cells.

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Section: The Mesodermal Potential Of Ascsmentioning

confidence: 99%

Adipose-Derived Stem Cells in Tissue Regeneration: A Review

2013

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“…Medium was exchanged three times per week for up to 6 weeks. ASC-MT cultures were prepared as previously described [24,28]. Briefly, 2.5 Â 10 3 ASCs were cultured in 25 ml hanging drops of osteogenic medium in Terasaki plates (VWR, Switzerland) for up to 6 days.…”

Section: Osteogenesis Of Samp6-derived Ascs In 3-d Culture Systemsmentioning

confidence: 99%

“…Total RNA was purified from either mouse ASCs or mouse bone tissue using TRIzol reagent and treated with TURBO DNase (Life Technologies) as previously described [20,28]. RNA (0.5 mg) was reverse transcribed to cDNA using superscript II (Life Technologies) and random hexanucleotide primers (Promega AG, Dübendorf, Switzerland), and quantification of mRNA expression performed using TaqMan Gene Expression Assays (Life Technologies) ( Table 1).…”

Section: Qrt-pcr Analysismentioning

confidence: 99%

Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis

et al. 2014

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a b s t r a c tAdipose-derived stromal cells (ASCs) are increasingly being used for orthopedic-based tissue engineering approaches due to their ability to readily undergo osteogenic differentiation. In the present study, we used in vitro and in vivo approaches to evaluate the use of ASCs as a treatment strategy for age-related osteoporosis. Molecular, histological and micro-computed tomography (micro-CT) based approaches confirmed that ASCs isolated from 18-week-old osteoporotic senescence-accelerated mice (SAMP6) were capable of undergoing osteogenesis when cultured in either silk fibroin (SF) scaffolds or scaffold-free microtissues (ASC-MT). A single intratibial injection of CM-Dil-labeled isogeneic ASCs or ASC-MT into SAMP6 recipients significantly improved trabecular bone quality after 6 weeks in comparison to untreated contralateral bones, as determined by micro-CT. Injected ASCs could be observed in paraffin wax bone sections at 24 h and 6 weeks post treatment and induced a significant increase in several molecular markers of bone turnover. Furthermore, a significant improvement in the osteogenic potential of osteoporotic patient-derived human bone marrow stromal cells (BMSCs) was observed when differentiated in conditioned culture media harvested from osteoporotic patient-derived human ASCs. These findings therefore support the use of ASCs as an autologous cell-based approach for the treatment of osteoporosis.

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“…[12] hBMSC-mediated matrix mineralization was visualized through Alizarin Red Ss taining after treatment with either 10 mm Ahp10 in the presence or absence of HTRA1, or the catalytically inactive mutant HTRA1 S328A (Figure 4). The data show that Ahp10 significantly inhibits HTRA1-mediated hBMSC osteogenesis and thus demonstrates the inhibition of HTRA1 by Ahp-cyclodepsipeptides in cell culture.F urthermore,the inhibitory effect was dose-dependent ( Figure S1 in the Supporting Information).…”

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confidence: 99%

Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors

et al. 2017

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The S1 serine protease family is one of the largest and most biologically important protease families.D espite their biomedical significance,g eneric approaches to generate potent, class-specific, bioactive non-covalent inhibitors for these enzymes are still limited. In this work, we demonstrate that Ahp-cyclodepsipeptides represent as uitable scaffold for generating target-tailored inhibitors of serine proteases.F or efficient synthetic access,wedeveloped apractical mixed solidand solution-phase synthesis that we validated through performing the first chemical synthesis of the two natural products Tasipeptin Aand B. The suitability of the Ahp-cyclodepsipeptide scaffold for tailored inhibitor synthesis is showcased by the generation of the most potent human HTRA protease inhibitors to date.W ea nticipate that our approach maya lso be applied to other serine proteases,thus opening new avenues for asystematic discovery of serine protease inhibitors.Serine proteases of the S1 family (trypsin/chymotrypsinlike) are one of the largest and biomedically relevant protease families.[1] In contrast to the design of covalent inhibitors or activity-based probes for this enzyme class, [2] generic approaches for designing potent, enzyme-class-specific,c ellactive,and non-covalent small-molecule inhibitors are highly limited and have been achieved only for distinct serine proteases.[3] Consequently,a lternative approaches for the systematic generation of such chemical probes are urgently required.Ahp-cyclodepsipeptides (also termed cyanopeptolins or peptolides) are aclass of over 100 peptidic natural products of non-ribosomal origin that display potent inhibitory properties against serine proteases.[4] All Ahp-cyclodepsipeptides are containing an Ahp (3-amino-6-hydroxy-2-piperidone) unit and an N-methyl aromatic amino acid at conserved positions in their 19-membered ring structure,while other residues are much less conserved (Figure 1a). Crystal structures of Ahpcyclodepsipeptides in complex with serine proteases indicate that inhibition is based on as ubstrate-like binding mode in which distinct amino acid residues occupy the S-and S'-pockets,h owever,p roteolytic cleavage does not occur (Figure 1b,S chechter and Berger nomenclature is used).[5] Accordingly,t hey act in as imilar manner to proteinaceous canonical serine protease inhibitors,w ith the conserved residues stabilizing the inhibitory fold, while the other less conserved residues define serine protease selectivity through optimal accommodation to the specific Sa nd S'-sites.T his suggests that Ahp-cyclodepsipeptides may represent as uit- Figure 1. Structural features and determinants of Ahp-cyclodepsipeptides for serine protease inhibition. a) Chemicals tructures of the natural product Ahp-cyclodepsipeptides TasA (1)a nd TasB (2). The red color indicates strictly conserved residues found in all so far known Ahp-cyclodepsipeptides; residues only rarely modified in Ahp-cyclodepsipeptides are depicted in green, and fully variable residues in blue. Note that th...

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Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

Cited by 62 publications

References 51 publications

Adipose-Derived Stem Cells in Tissue Regeneration: A Review

Adipose-Derived Stem Cells in Tissue Regeneration: A Review

Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis

Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors

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